A Multi-Center, Open-Label, Phase I, Dose-Escalation and Safety Study of 188Re-PTI-6D2 in Patients With Metastatic Melanoma
Patients with confirmed Stage III (unresectable) or Stage IV melanoma who meet all
eligibility criteria will undergo thorough physical examination and baseline tumor imaging
to document baseline tumor measurements. Patients will be allowed to check in to the study
center either the evening prior to dosing (Study Day 0) or the day of dosing (Study Day 1)
based upon the principal investigators (PIs) discretion. All patients will be dosed and
monitored as inpatients during the study.
Patients will receive an intravenous (IV) infusion of 188Re-PTI-6D2. Patients will undergo
serial gamma scans at specified time points. Blood samples will be obtained prior to dosing
and at specified intervals for PK measurements of the mAb as well as for measurement of
serum radioactivity. Urine will be collected to measure excreted radioactivity. Patients
will be closely monitored for safety throughout the duration of the study. Patients will
remain at the study center for 48-72 hours after infusion of the radiolabeled dose to allow
adequate time for post-treatment safety observation and rhenium decay. No investigational or
commercial agents or therapies other than the study agent may be administered with the
intent to treat the patient's malignancy during the inpatient treatment period.
After three evaluable patients have been followed for a minimum of 2-6 weeks after
188Re-PTI-6D2 infusion, the Principal Investigator and the PTI Medical Monitor will review
safety data for patients at the current dose level. If there is no evidence of a
dose-limiting toxicity, the dose of 188Re-PTI-6D2 will be escalated for the next cohort of
patients. Dose escalation of 188Re-PTI-6D2 will occur according to the following titration
Level 1 = 20-30 mCi 188Re-PTI-6D2 / 10 - 50 mg of antibody
Level 2 = 40-60 mCi 188Re-PTI-6D2 / 10 - 50 mg of antibody
Level 3 = 75-100 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Level 4 = 125-150 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Level 5 = 175-200 mCi 188Re-PTI-6D2 / 50 - 100 mg of antibody
Dose-limiting toxicity will be defined as the following: Grade 4 hematological toxicity; ≥
Grade 3 non-hematological toxicity; or any adverse event that results in permanent
discontinuation of the infusion. If at any time Grade 5 toxicity is observed, accrual will
be suspended until further review. If 0 out of 3 patients experience DLT, the next cohort of
3 patients will be enrolled at the next dose level. If 1 out of 3 patients experience a
dose-limiting toxicity, an additional three evaluable patients will be enrolled at the
current dose level.
Dose escalation occurs until the maximum tolerated dose is determined. The MTD is defined as
the dose preceding the dose at which 2 of 3 or 2 of 6 patients experience DLT.
Safety will be evaluated by vital signs (blood pressure, heart rate, respiratory rate and
temperature), physical examinations, electrocardiograms (EKGs), clinical laboratory tests
and adverse event monitoring. Laboratory studies will include hematology, chemistry and
urinalysis at baseline, at the end of the inpatient treatment period, and at 2 weeks and 6
weeks after the infusion of the 188Re-PTI-6D2 dose. If hematological recovery has not
occurred by week 6, patients will follow-up monthly until hematological recovery. In
addition, thyroid function tests will be performed at baseline and at 6 weeks after
infusion; then monthly until recovery (if has not occurred). Human anti-murine antibodies
(HAMA) will be measured at baseline, 2 weeks, and 6 weeks after infusion .
Biodistribution of 188Re-PTI-6D2 will be evaluated by whole body imaging with a gamma camera
immediately after infusion (0 - 2 hrs.), at 2.5 - 5 hours, at 6 - 8 hours, and 24 hours
post-infusion. Whole body imaging at 48 and 72 hours post-infusion may be conducted at the
discretion of the PI. Urine will be collected to measure cumulative radioactivity excretion
up to 48-72 hours post-infusion (depending on the hospital discharge date). Pharmacokinetics
of the mAb and radioactivity will be determined from blood samples taken through 48-72 hours
post-infusion (depending on the hospital discharge date). Dosimetry calculations will be
performed to determine estimated absorbed radiation doses to critical organs and to tumor.
Patients will be discharged from the study unit 48-72 hours after infusion with
188Re-PTI-6D2 or later as determined by the Investigator's clinical judgment. Patients will
be required to return for post-treatment follow-up visits approximately 2 and 6 weeks (± two
days) after infusion for safety monitoring. Ongoing follow-up visits will continue until
disease progression every 4 weeks. Tumor measurements will be performed at baseline, and all
follow-up visits to assess for tumor response. Patients with unacceptable adverse events
will have events followed until resolution.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the maximum tolerated dose (MTD) of 188Re-PTI-6D2 in patients with metastatic melanoma
Eithan Galun, M.D.
Hadassah Hebrew University Hospital
Israel: Ministry of Health